A combination of two immunotherapy drugs added to standard chemotherapy before surgery showed encouraging activity for patients with high-risk, early-stage HER2-negative breast cancer, according to phase 2 clinical trial results from the ongoing I-SPY2 clinical trial platform published on July 30. The treatment regimen will not advance for further study due to excess toxicities found when combining the two immunotherapies. However, researchers said the outcome demonstrates potential for improved outcomes with novel immunotherapy combinations.
The study results were published in JAMA Oncology and involved dual immunotherapies given alongside conventional drugs prior to surgery. Cemiplimab blocks the anti−programmed cell death 1 (PD-1) protein on T cells, preventing tumor cells from hiding from immune attack. Fianlimab blocks the lymphocyte-activation gene 3 (LAG-3) protein on T cells, stimulating the immune system to target hidden cancer cells. Both were administered every three weeks with weekly systemic chemotherapies consisting of paclitaxel before doxorubicin and cyclophosphamide.
The full drug regimen—referred to as PCF—was tested in adults with stage II or III HER2-negative breast cancer at high risk of recurrence, including triple-negative and hormone receptor–positive/HER2-negative disease. Seventy-eight participants were randomly assigned to the PCF group and 350 participants received standard care as a control group. The dual-checkpoint regimen met I-SPY2's prespecified threshold for probability of success in a future phase 3 trial.
The primary endpoint was pathologic complete response (pCR), meaning no residual invasive cancer detected at surgery. Estimated pCR rates improved from 21% with standard therapy to 44% with PCF among all HER2-negative patients; in triple-negative cases, pCR rates increased from 29% to 53%, while hormone receptor–positive/HER2-negative cases saw an increase from 14% to 36%. Isaacs said, "Ultimately, these results show that this particular regimen was very effective. This establishes a proof of principle for dual targeting, which is promising because there are new drugs being developed, such as bispecific antibodies that can hit two targets with one drug that might have lower toxicity and a similar type of efficacy."
Investigators also reported strong activity among patients whose tumors tested positive for ImPrint—a gene immune-response test—with notably high pCR rates: including up to 83% in triple-negative breast cancer and up to 91% in hormone receptor–positive/HER2-negative disease.
While efficacy results were promising, safety concerns emerged: adrenal glands showed decreased hormone production in about one-fifth of patients receiving PCF; serious grade three or four events occurred in over ten percent; diabetes developed in four percent; many endocrine events occurred weeks after completion of therapy. Isaacs said, "Given these trial results, we may look at alternate dosing of the drugs or look at novel ways to hit those two immune targets with different drugs that would be better tolerated and offer people higher efficacy... The bottom line is that we want to individually treat people with the drugs that they need and avoid toxicities for optimal outcomes."
